"METHOD OF PREPARATION OF 1,3-DIPHENYLPROP-2-EN-1-ONE COMPOUNDS"

Abstract

The present invention relates to a method of preparation of 1,3-dipheriylprop-2-en-l-one compounds substituted by a carboxyalkyloxy or carboxyalkylthio group of the following general formula: in which Xi, X2, Xs, X4,Xs; Ri, Rs, R4, Rs; Gi, Ga, G4, Gs are such as herein described in the specification.

Full Text

PREPARATION OF l,3-DIPHENYLPROP-2-EN-l-ONE DERIVATIVES
The present invention relates to a method of preparation of 1,3-diphenylprop-2-en-l-one compounds substituted by a carboxyalkyloxy or carboxyalkylthio group.
The invention relates to a novel method for the preparation 01 1,0-diphenylprop-2-en-1-one derivatives substituted on one of the two phenyl groups by a carboxyalkyloxy group or a carboxyalkylthio group.

Generally, 1,3-diphenylpropen-1-ones are prepared by a condensation reaction of an aldehyde with a ketone in a Claisen-Schmidt reaction (March J., 1992, "Advanced Organic Chemistry", Fourth Edition, 940, Wiley Interscience).
Classically, 1,3-diphenylprop-2-en-1-ones substituted by a carboxyalkyloxy group are obtained by said method from starting materials (aldehyde and ketone) which are selected in such a way as to be substituted by a carboxyalkyloxy group or by the corresponding ester. This sequence of steps may be summarized by one of the following reaction diagrams :
(Formula Removed)
However, the acidic nature of the compound so obtained and the frequent presence in the reaction medium of secondary products and unreacted starting materials make purification by recrystallization or silica gel chromatography difficult and result in a significant reduction in the yield.

Thus, the use of this synthetic strategy for preparing compounds cited as
example 1 and example 3 herein has not made it possible to achieve overall yields
greater than 10%.
The inventors have now developed a method which is simple to carry out
whereby 1,3-diphenyl-2-en-1-ones substituted by a carboxyalkloxy group or a
carboxyalkylthio group can be obtained with high yields. The method differs from
the aforementioned synthesis in that the carboxyalkloxy or carboxyalkylthio group
is introduced in the form of the tert-butyl or isopropyl ester by reaction with a 1,3-
diphenyl-2-en-1-one derivative substituted by a hydroxyl or thiol group. The latter
is generally obtained by a Claisen-Schmidt reaction.
One embodiment of the inventive method is based on the use of the acidlabile
protective group of carboxylic acid, for example of the type tert-butyl or
isopropyl. The inventors have shown that said group can be added and cleaved
under conditions compatible with the chemical structure of diphenyl-1,3-prop-2-en-
1-ones. They have put these advantages to use to develop a novel method of
synthesis which is the object of the invention.
1,3-diphenylprop-2-en-1-ones substituted by a carboxyalkyloxy group or a
carboxyalkylthio group which are obtained in this manner are of major interest in
the pharmaceutical or cosmetics field. In fact, said compounds concurrently
display PPAR activator, antioxidant and anti-inflammatory properties and, as such,
have a high therapeutic or prophylactic potential and in particular can be used for
the treatment or prevention of cerebrovascular diseases, cardiovascular diseases,
syndrome X, restenosis, diabetes, obesity, hypertension, inflammatory disorders,
cancers or neoplasms (benign or malignant tumors), neurodegenerative,
dermatologic diseases and disorders related to oxidative stress, for the prevention
or treatment of the effects of ageing in general and for example skin ageing,
particularly in the field of cosmetics (appearance of wrinkles, etc.).
The invention is therefore directed at providing a method of preparation of
1,3-diphenylprop-2-en-1-one derivatives substituted on one of the two phenyl
groups by a carboxyalkyloxy or carboxyalkylthio group which is easy to carry out
and which gives high yields.
This objective and others are attained by the invention which in particular
has as object a method for preparing 1,3-diphenylprop-2-en-1-one derivatives
substituted by a carboxyalkyloxy or carboxyalkylthio group, comprising a step,
hereinbelow called (i), of contacting at least one 1,3-diphenylprop-2-en-1-one
derivative substituted on one of the phenyl groups by a hydroxyl or thiol group with
at least one halogenated compound represented by general formula (II) below, in
which Y represents a halogen atom, R is a C1-C24 alkyl chain (containing from 1
to 24 carbon atoms) and R' is an acid-labile protective group of the carboxylic acid.
Said step may be summarized by one of the following reaction diagrams :
(Figure Removed)
R = alkyl chain, R' = acid-labile protective group
Step (i): first illustration
(Figure Removed)
alkyl chain R' = acid-labile protective group
Step (i): second illustration
Said step is advantageously carried out at a temperature comprised
between 25 and 120°C and more preferably between 80 and 120°C, preferably at
atmospheric pressure, in the presence of a catalyst, such as cesium or potassium
carbonate.
In a preferred manner, said step is repeated by several additions of the
halogenated compound represented by general formula (II) and optionally the
catalyst, such as cesium or potassium carbonate, advantageously until
disappearance of the 1,3-diphenylprop-2-en-1-one derivative substituted on one of
the phenyl groups by a hydroxyl or thiol group.
The alkyl chain R of the halogenated compound represented by general
formula (II) designates a hydrocarbon chain, saturated or not, linear or cyclic
containing from 1 to 24, preferably from 1 to 10 carbons and more particularly one
carbon atom. Said chain can be substituted by one or more hydrocarbon groups,
saturated, linear or cyclic containing from 1 to 12 carbon atoms, advantageously
from 1 to 6 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,
neopentyl, n-hexyl and more particularly methyl.
Preferably, the carboxylic acid protective group is selected in the group
consisting of acid-labile functions of the type C1 to C5 alkyl (containing from 1 to 5
carbon atoms) substituted at the carbon atom linked to the carboxylic function by
one or two linear or branched alkyl groups containing from 1 to 4 carbon atoms.
More preferably, the protective group is selected from among tert-butyl and
isopropyl groups.
In the present description, the terms "tert-butyl and isopropyl groups" are
employed, but it must be understood that they can be generalized to any other
protective group of carboxylic acid such as defined hereinabove.
Avantageously, the 1,3-diphenylprop-2-en-1-one derivative substituted by a
hydroxyl or thiol group which is used in step (i) described hereinabove is obtained
by a Claisen-Schmidt reaction in acidic or basic medium of a compound of the
type acetophenone with a thio- or hydroxy-benzaldehyde derivative, or of a thio- or
hydroxy-acetophenone derivative with a compound of the benzaldehyde type.
Subsequent to step (i) described hereinabove, the inventive method
comprises a step (ii) of preparing the carboxyalkyloxy or carboxyalkylthio
derivative of 1,3-diphenylprop-2-en-1-one by acid hydrolysis of the ester obtained
in step (i).
Said step (ii) may be summarized by one of the following reaction diagrams
(Figure Removed)
G = OorS,
R = alkyl chain and R' = protective group
Step (ii): first illustration
G = O or S
R = alkyl chain and R' = protective group
Step (ii): second illustration
Advantageously, said acid hydrolysis step is carried out by contacting a 1,3-
diphenylprop-2-en-1-one derivative substituted by an alkyloxycarbonylalkyloxy or
alkyloxycarbonylalkylthio group with trifluoroacetic acid. Generally, the amount of
trifluoroacetic acid is from 1 to 20 equivalents, and preferably from 8 to 12
equivalents. Advantageously, said step is carried out at a temperature of 0 to
100°C and more preferably from 18 to 25°C, and preferably at atmospheric
pressure.
More specifically, then, the invention describes the preparation of 1,3-
diphenylprop-2-en-1-ones substituted by a carboxyalkyloxy group or a
carboxyalkylthio group. The interest of said method lies in the combination of two
synthetic steps : synthesis of tert-butyl or isopropyl esters (or any other protective
group) from 1,3-diphenylprop-2-en-1-ones substituted on one of the phenyl groups
by a hydroxyl or thiol group, followed by acid hydrolysis of the intermediate esters
so prepared.
The tert-butyloxycarbonylalkyl or isopropyloxycarbonylalkyl group is added
easily, with a high yield, by alkylation of a chemical precursor (hydroxy-1,3-
diphenylprop-2-en-1-one or the sulfated analog of same) with a halogenated
derivative. The tert-butyl or isopropyl ester intermediate so obtained can be easily
purified, in particular by silica gel chromatography or by recrystallization.
The tert-butyl or isopropyl ester is cleaved to the corresponding acid by the
action of trifluoroacetic acid. This method, adapted to the cleavage of the tertbutyl
or isopropyl group, makes it possible to achieve complete conversion of the
ester to the corresponding acid. The inventors have discovered that said method
is compatible with the chemical structure of 1,3-diphenylprop-2-en-1-ones.
Consequently, it does lead to the formation of degradation products and it allows
production of the acids at higher yields than those classically observed.
The three steps that can be carried out in the scope of the invention may be
summarized as follows.
First step : synthesis of the chemical precursor
The chemical precursor of the type hydroxy-1,3-diphenylprop-2-en-1-one or
the sulfated analog of same can be prepared by the classical Claisen-Schmidt
reaction in acidic or basic medium :
(Figure Removed)
Compounds of the type acetophenone, hydroxy-acetophenone (or the
sulfated analog of same), benzaldehyde and hydroxy-benzaldehyde (or the
sulfated analog of same) used in said reaction can optionally be substituted by
phenyl groups. Said substituents are selected more particularly in the group
consisting of a halogen atom, an alkyl group, a thionitroso group, and an alkyloxy
or alkylthio group.
The conditions in which to carry out said reaction in acidic or basic medium
are familiar to those skilled in the art and can vary widely.
In an advantageous manner, said two compounds are contacted in
stoichiometric proportions. Contact is preferably carried out at room temperature
(between approximately 18°C and 25°C) and at atmospheric pressure.
In basic medium, the reaction is preferably carried out in the presence of a
strong base, such as an alkaline metal hydroxide, like sodium hydroxide, or an
alkaline metal alcoholate such as sodium ethylate.
In acidic medium, the reaction is preferably carried out in the presence of a
strong acid, such as hydrochloric acid.
Advantageously, the synthesis in basic medium can be carried out in the
following manner:
One molar-equivalent of the ketone and 1 molar-equivalent of the aldehyde
are dissolved in a water-alcohol solution of sodium hydroxide at 20 molar
equivalents. The mixture is stirred for 6 to 48 hours and preferably 16 to 20 hours
at a temperature of 0 to 100°C and preferably 18 to 25°C. The medium is then
acidified (in particular to a pH of approximately 2), in particular with hydrochloric
acid.
The expected hydroxy-1,3-diphenylprop-2-en-1-one (or the sulfated analog of
same) can be obtained by precipitation or solid/liquid extraction after evaporation
of the reaction medium. It can then be purified by silica gel chromatography or by
recrystallization.
Advantageously, the synthesis in acidic medium can be carried out in the
following manner:
One molar-equivalent of the ketone and 1 molar-equivalent of the aldehyde
are dissolved in an ethanol solution saturated with gaseous hydrochloric acid. The
mixture is stirred at a temperature of 0 to 100°C and preferably at a temperature of
18 to 25°C for 1 to 24 hours and preferably 1 to 6 hours, preferably at atmospheric
pressure. The solvent is eliminated in particular by vacuum evaporation. The 1,3-
diphenylprop-2-en-1-one is purified, in particular by chromatography on silica gel.
Second step : preparation of the tert-butyl or isopropyl ester
(Figure Removed)
G representing an oxygen or sulfur atom,
Y representing a halogen atom,
R is an alkyl chain, preferably C1 to C6
R' = tert-butyl or isopropyl
The reaction can be carried out in the following manner:
One molar-equivalent of hydroxy-1,3-diphenylprop-2-en-1-one (or the sulfated
analog of same) is dissolved in a solvent, preferably in acetonitrile or acetone, 1 to
10 equivalents and preferably 4 to 6 equivalents of cesium or potassium carbonate
are added followed by addition of the derivative of type halogenated tert-butyl or
isopropyl ester (1 to 20 molar-equivalents and preferably 4 to 8 molar-equivalents
and even more preferably 6 equivalents). The mixture is heated with (vigorous)
stirring at a temperature of 25 to 120°C and preferably 100°C for 1 to 24 hours and
preferably 10 to 14 hours and even more preferably 10 hours, generally at
atmospheric pressure. The solvent is eliminated, in particular by vacuum
evaporation. The reaction medium is optionally reacted again with 3 to 6 molarequivalents
of the halogenated derivative and 3 to 5 molar-equivalents of cesium
or potassium carbonate, said operation can be repeated until complete
disappearance of the starting material.
The 1,3-diphenylprop-2-en-1-one substituted by a tert-butyloxycarbonylalkyloxy,
tert-butyloxycarbonylalkylthio, isopropyloxycarbonylalkyloxy, or
isopropyloxycarbonylalkylthio group is purified, in particular by silica gel
chromatography.
Third step : preparation of the acid from the tert-butyl or isopropyl ester
(Figure Removed)
G and R are such as defined hereinabove.
R' = tert-butyl or isopropyl
(Figure Removed)
G and R are such as defined hereinabove.
R' = tert-butyl or isopropyl
One molar-equivalent of the 1,3-diphenylprop-2-en-1-one substituted by a
tert-butyloxycarbonylalkyloxy group, by a tert-butyloxycarbonylalkylthio group, by
an isopropyloxycarbonylalkyloxy group or by an isopropyloxycarbonylalkylthio
group is dissolved in a solvent, such as dichloromethane. 1 to 20 equivalents and
preferably 8 to 12 equivalents of acid and more preferably 10 equivalents of acid,
preferably trifluoroacetic acid, are added. The mixture is stirred vigorously at a
temperature of 0 to 100°C, preferably 18 to 25°C, for 1 to 24 hours and preferably
8 to 14 hours and more preferably 12 hours, preferably at atmospheric pressure.
The solvent is eliminated, in particular by vacuum evaporation. The 1,3-
diphenylprop-2-en-1-one substituted by a carboxyalkyloxy or carboxyalkylthio
group is purified, in particular by silica gel chromatography. Preferably, the
reaction is carried out at atmospheric pressure.
This method can advantageously be implemented for preparing compounds
described in the French patent application FR 02 08571 filed by the Applicant on
8th July 2002. Said compounds are represented by the general formula :
(Figure Removed)
in which :
X1 represents a halogen or a -R1 group or a group corresponding to the following
formula : -G1-R1;
X2 represents a hydrogen atom or a thionitroso group or an alkyloxy group or an
alkylcarbonyloxy group or an alkylthio group or an alkylcarbonylthio group;
X3 represents a -R3 group or a group corresponding to the following formula: -GSRS;
X4 represents a halogen or a thionitroso group or a -R4 group or a group
corresponding to the following formula : -G4-R4;
X5 represents a -R5 group or a group corresponding to the following formula :
G5-R5;
R1, R3, R4, R5, which are the same or different, represent a hydrogen atom or an
alkyl group substituted or not by a carboxylic acid function;
G1, G3, G4, G5, which are the same or different, represent an oxygen or sulfur
atom;
with one of the groups X1, X3, X4 or X5 corresponding to the formula -G-R, in
which R is an alkyl group containing a carboxylic acid function.
Advantageously, said synthetic method allows the preparation of
compounds represented by general formula (I) in which none of the groups X1,
X2, X3 and X4 is a hydroxyl or thiol group.
In a preferred manner, said method allows the preparation of compounds
represented by general formula (I) for which at least one of the groups R3, R4 and
R5 represents an alkyl group containing a carboxylic acid function.
In a preferred manner, R4 is an alkyl group containing a carboxylic acid
function.
In a preferred manner, R4 is an alkyl group containing a carboxylic acid
function and X3 and X5 are unsubstituted alkyls.
In a more preferred manner, X4 is a carboxydimethylmethyloxy or
carboxydimethylmethylthio group.
In a preferred manner, G4 is an oxygen atom and R4 is an alkyl group
containing a carboxylic acid function.
In a preferred manner, G4 is an oxygen atom and R4 is an alkyl group
containing a carboxylic acid function and X3 and X5 are unsubstituted alkyls.
In a more preferred manner, X4 is a carboxydimethylmethyloxy group.
In a more preferred manner, X4 is a carboxydimethylmethylthio group.
Derivatives represented by general formula (I) such as described
hereinabove can adopt the cis or trans conformation.
Advantageously, X3, X4 and X5 are not hydrogen atoms.
In the spirit of the invention, the term "alkyl" denotes a saturated
hydrocarbon group, linear, branched or cyclic, halogenated or not, more
particularly containing from 1 to 24, preferably 1 to 10, carbon atoms such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, nhexyl.
C1-C2 or C2-C7groups are particularly preferred. Methyl and ethyl groups
are more particularly preferred.
The term thionitroso refers to a nitroso group linked to the aromatic ring by
means of a sulfur atom.
The term halogen represents a chlorine atom or a bromine atom or an
iodine atom or a fluorine atom.
The term alkyloxy refers to an alkyl chain linked to the ring by means of an
oxygen atom. The alkyl chain is defined hereinabove.
The term alkylthio refers to an alkyl chain linked to the ring by means of a
sulfur atom (thioether bond). The alkyl chain is defined hereinabove.
The compounds or intermediate products (esters) preferably obtained by
the inventive method are shown below with their corresponding formulas :
1-[4-chlorophenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1-one
o
1-[4-chlorophenyl]-3-[3,5-dimethyl-4-
isopropyloxycarbonyldimethylmethyloxyphenyl]prop-2-en-1-one
1-[4-chlorophenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-en-
1-one
1-[4-methylthiophenyl]-3-[4-carboxydimethylmethyloxyphenyl]prop-2-en-1-one
1-[4-carboxydimethylmethyloxyphenyl]-3-[4-chlorophenyl]prop-2-en-1-one
1-[4-carboxydimethylmethylthiophenyl]-3-[4-methylthiophenyl]prop-2-en-1-one
1-[4-carboxydimethylmethyloxyphenyl]-3-[4-methylthiophenyl]prop-2-en-1-one
1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1-one
o
1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-
isopropyloxycarbonyldimethylmethyloxyphenyl]prop-2-en-1-one
1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-
en-1-one
(Figure Removed)
1-[2-methoxyphenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1-one
1-[2-methoxyphenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-
en-1-one
1-[4-hexyloxyphenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1-one
1-[4-hexyloxyphenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-
en-1-one
1-[2-methyloxy-4-chlorophenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1-one
Q
1-[2-methyloxy-4-chlorophenyl]-3-[3,5-dimethyl-4-
carboxydimethylmethyloxyphenyl]prop-2-en-1-one
1-[4-heptylphenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1-one
1-[4-heptylphenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-(Figure Removed)
1-[4-bromophenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1-one
1-[4-bromophenyl]-3-[3,5-dimethyl-4-carboxy
dimethylmethyloxyphenyl]prop-2-en-1-one
Other aspects and advantages of the invention will become apparent in the
following examples, which are given for purposes of illustration and not by way of
limitation.
EXAMPLES
1 - Description of the general synthetic methods :
General method 1 :
Synthesis of hydroxy-1,3-diphenylprop-2-en-1-ones :
One molar-equivalent of hydroxy-acetophenone (or the sulfated analog of same)
and 1 molar-equivalent of aldehyde, or 1 molar-equivalent of hydroxybenzaldehyde
(or the sulfated analog of same) and 1 molar-equivalent of ketone
are dissolved in an ethanol solution saturated with gaseous hydrochloric acid. The
mixture is stirred at room temperature for 1 to 6 hours and the solvent is eliminated
by vacuum evaporation. The hydroxy-1,3-diphenylprop-2-en-1-one is purified by
silica gel chromatography or by recrystallization.
General method 2 :
Alkylation of hydroxy-1,3-diphenylprop-2-en-1 -ones :
One molar-equivalent of hydroxy-1,3-diphenylpropen-1 -one (or the sulfated analog
of same) is dissolved in acetonitrile and 3 to 6 molar-equivalents of the
halogenated derivative followed by 3 to 5 molar equivalents of potassium
carbonate are added. The reaction medium is stirred vigorously under reflux for
about 10 hours. The salts are eliminated by filtration.
Optionally, the reaction medium is reacted again with 3 to 6 molar-equivalents of
the halogenated derivative and 3 to 5 molar-equivalents of potassium carbonate.
This operation can be repeated until complete disappearance of the starting
material.
Solvent and excess reagent are eliminated by vacuum evaporation and the
expected product is purified by silica gel chromatography.
General method 3:
Acid hydrolysis of the tert-butyl esters of 1,3-diphenylprop-2-en-1-ones by
trifluoroacetic acid :
One molar-equivalent of 1,3-diphenylprop-2-en-1-one tert-butyl ester is dissolved
in dichloromethane, then 10 molar-equivalents of trifluoroacetic acid are added
and the mixture is stirred at room temperature for 12 hours. The product which
forms is purified by silica gel chromatography or by recrystallization.
2 - Examples :
Example 1 : Synthesis of
1-f4-chlorophenvn-3-f3.5-dimethvl-4-carboxvdimethvlmethvloxvphenvnprop-
2-en-1-one
(Figure Removed)
The method enabled the preparation of said compound with an overall yield of
56%.
Synthesis of the chemical precursor:
1-[4-chlorophenyl]-3-[3,5-dimethyl-4-hydroxyphenyl]prop-2-en-1-one
(Compound 1)
This compound was synthesized from 4-chloroacetophenone and 3,5-dimethyl-4-
hydroxybenzaldehyde according to general method 1 described hereinabove.
Purification was by silica gel chromatography (cyclohexane/ethyl acetate 95:5).
Yield :91%
1H NMR CDCI3 8 ppm : 2.30 (s, 6H), 7.32 (s, 2H), 7.34 (d, J = 15.25Hz, 1H), 7.47
(d, J = 8.86HZ, 2H), 7.75 (d, J = 15.26 Hz, 1H), 7.97 (d, J = 8.86Hz, 2H).
Synthesis of the tert-butvl ester:
1-[4-chlorophenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1 -one (Compound 2)
This compound was synthesized from 1-[4-chlorophenyl]-3-[3,5-dimethyl-4-
hydroxyphenyl]prop-2-en-1-one (Compound 1) and tert-butyl bromoisobutyrate
according to general method 2 described hereinabove.
Purification was by silica gel chromatography (cyclohexane/ethyl acetate 90:10).
Yield : 70%
Acid hydrolysis of the tert-butvl ester:
1-[4-chlorophenyl]
-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-en-1-one
(Compound 3)
This compound was synthesized from 1-[4-chlorophenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1 -one (Compound 2)
according to general method 3 described hereinabove.
Purification was by silica gel chromatography (dichloromethane/methanol 98:2).
Yield : 88%
1H NMR DMSO 6 ppm : 1.39 (s, 6H), 2.22 (s, 6H), 7.58 (s, 2H), 7.67-7.62 (m, 3H),
7.82 (d, J = 15.5 Hz, 1H), 8.17 (d, 2H), 12.96 (s, 1H)
MS (Maldi-Tof): 373.3 (M+1)
Example 2 : Synthesis of
1-r2-methoxv1-3-r3.5-dimethvl-4-carboxvdimethvlmethvloxvDhenvnprop-2-en-
1-one
The method enabled the preparation of said compound with an overall yield of
20%.
Synthesis of the chemical precursor:
1 -[2-methoxyphenyl]
-3-[3,5-dimethyl-4-hydroxyphenyl]prop-2-en-1-one (Compound 4)
This compound was synthesized from 2-methoxyacetophenone and 3,5-dimethyl-
4-hydroxybenzaldehyde according to general method 1 described hereinabove.
Purification was by silica gel chromatography (cyclohexane/ethyl acetate 80:20).
Yield : 66%
1H NMR CDCI3 6 ppm : 2.27 (s, 6H), 3.87 (s, 3H), 6.97-7.05 (m, 2H), 7.19 (d,
1H, J = 15.96 Hz), 7.22 (s, 2H), 7.44 (m, 1H), 7.51 (d, 1H, J = 15.48 Hz), 7.56
(dd, 1H, J = 1.86 Hz, J = 7.5 Hz)
Synthesis of the tert-butvl ester:
1-[2-methoxyphenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1 -one (Compound 5)
This compound was synthesized from 1-[2-methoxyphenyl]-3-[3,5-dimethyl-4-
hydroxyphenyl]prop-2-en-1-one (Compound 4) and tert-butyl bromoisobutyrate
according to general method 2 described hereinabove.
Purification was by silica gel chromatography (cyclohexane/ethyl acetate 80:20).
Yield: 41%
Acid hydrolysis of the tert-butvl ester:
1 -[2-methoxyphenyl]
-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-en-1-one
(Compound 6)
This compound was synthesized from 1-[2-methoxyphenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1 -one (Compound 5)
according to general method 3 described hereinabove.
Purification was by silica gel chromatography (dichloromethane/methanol 98:2).
Yield : 70%
1H NMR DMSO 8 ppm : 1.38 (s, 6H), 2.19 (s, 6H), 3.93 (s, 3H), 7.05 (m, 1H),
7.20 (d, J = 8.31Hz, 1H), 7.25 (d, J = 15.5Hz, 1H), 7.37 (d, J = 15.5Hz, 1H), 7.39
(s, 2H), 7.46 (d, J = 7.2Hz, 1H), 7.53 (m, 1H), 12.93 (s, 1H)
MS (ES-MS): 367.1 (M-1)
Example 3 :
Synthesis of la 1-r4-methvlthiophenvn
-3-r3.5-dimethvl-4-carboxvdimethvlmethvloxyphenvnproD-2-en-1-one
The method enabled the preparation of said compound with an overall yield of
49%.
Synthesis of the chemical precursor:
1 -[4-methylthiophenyl]
-3-[3,5-dimethyl-4-hydroxyphenyl]prop-2-en-1-one (Compound 7)
This compound was synthesized from 4-methylthioacetophenone and 3,5-
dimethyl-4-hydroxybenzaldehyde according to general method 1 described
hereinabove.
Purification was by silica gel chromatography (cyclohexane/ethyl acetate 80:20).
Yield : 86%
1H NMR DMSO 8 ppm : 1.22 (s, 6H), 2.54 (s, 3H), 7.36 (d, J = 8.20Hz, 2H), 7.48
(s, 2H), 7.62 (d, J = 15.7Hz, 1H), 7.74 (d, J = 15.7Hz, 1H), 8.10 (d, J = 8.20Hz,
2H), 8.92(s, 1H)
Synthesis of the tert-butvl ester
1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1 -one (Compound 8)
This compound was synthesized from 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-
hydroxyphenyl]prop-2-en-1-one (Compound 7) and tert-butyl bromoisobutyrate.
1 -[4-methylthiophenyl]-3-[3,5-dimethyl-4-hydroxyphenyl]prop-2-en-1 -one was
dissolved in acetonitrile and 3 molar-equivalents of potassium carbonate and 3
molar-equivalents of tert-butyl bromoisobutyrate were then added. The mixture
was stirred at 80°C for 12 hours, then brought to room temperature. The salts
were eliminated by filtration. Three molar-equivalents of potassium carbonate and
3 molar-equivalents of tert-butyl bromoisobutyrate were added. The mixture was
reacted for another 12 hours, then brought to room temperature. The salts were
eliminated by filtration. Three molar-equivalents of potassium carbonate and 3
molar-equivalents of tert-butyl bromoisobutyrate were added. The mixture was
stirred at 80°C for 12 hours and the salts were eliminated by filtration. The
solvents were eliminated by vacuum evaporation.
Purification was by silica gel chromatography (cyclohexane/ethyl acetate 90:10).
Yield : 74%
Acid hydrolysis of the tert-butvl ester
1 -[4-methylthiophenyl]
-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-en-1-one
(Compound 9)
This compound was synthesized from 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-
tert-butyloxycarbonyldimethylmethyloxyphenyl]prop-2-en-1 -one (Compound 8)
according to general method 3 described hereinabove.
Purification was by silica gel chromatography (dichloromethane/methanol 98:2)
Yield: 81%
1H NMR DMSO 8 ppm : 1.39 (s, 6H), 2.22 (s, 6H), 2.57 (s, 3H), 7.40 (d, J =
8.55Hz, 2H), 7.57 (s, 2H), 7.62 (d, J = 15.5Hz, 1H), 7.83 (d, J = 15.5Hz, 1H), 8.10
(d, J = 8.55Hz, 2H), 12.97 (s, 1H)
MS (ES-MS): 383.3 (M-1)
Example 4:
Synthesis of 1-r4-hexvloxvphenvn
-3-r3.5-dimethvl-4-carboxvdimethvlmethvloxvphenvnprop-2-en-1-one
The method enabled the preparation of said compound with an overall yield of
24%.
Synthesis of the chemical precursor:
1 -[4-hexyloxyphenyl]
-3-[3,5-dimethyl-4-hydroxyphenyl]prop-2-en-1-one (Compound 10)
This compound was synthesized from 4-hexyloxyacetophenone and 3,5-dimethyl-
4-hydroxybenzaldehyde according to general method 1 described hereinabove.
The product crystallized at the end of the reaction and was dried. Yield : 63%
1H NMR DMSO 8 ppm : 0.88 (m, 3H), 1.28-1.43 (m, 6H), 1.72 (m, 2H), 2.21 (s,
6H), 4.05 (t, J = 6.42HZ, 2H), 7.40 (d, J = 8.43Hz, 2H), 7.48 (s, 2H), 7.57(d, J =
15.24hz, 1H), 7.72 (d, J = 15.24Hz, 1H), 8.12 (d, J = 8.43Hz, 2H), 8.89 (s, 1H)
Synthesis of the tert-butvl ester:
1 -[4-hexyloxyphenyl]
-3-[3,5-dimethyl-4-tert-butyloxycarbonyldimethylmethyloxyphenyl]prop-2-en-1-
one (Compound 11)
This compound was synthesized from 1-[4-hexyloxyphenyl]-3-[3,5-dimethyl-4-
hydroxyphenyl]prop-2-en-1-one (Compound 10) and tert-butyl bromoisobutyrate
according to general method 2 described hereinabove.
Purification was by silica gel chromatography(cyclohexane/ethyl acetate 95:5).
Yield : 75%
Acid hydrolysis of the tert-butvl ester:
1 -[4-hexyloxyphenyl]
-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-en-1-one
(Compound 12)
This compound was synthesized from 1-[4-hexyloxyphenyl]-3-[3,5-dimethyl-4-terbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1-one (Compound 11)
according to general method 3 described hereinabove.
Purification was by recrystallization in methanol. Yield : 51%
1H NMR DMSO 5 ppm : 0.88 (t, J = 6.33Hz, 3H), 1.30 (m, 4H), 1.39 (s, 6H), 1.44
(m, 2H), 1.73 (m, 2H), 2.22 (s, 6H), 4.06 (t, J = 6.30Hz, 2H), 7.06 (d, J = 8.61 Hz,
2H), 7.56 (s, 2H), 7.58 (d, J = 15.5Hz, 1H), 7.82 (d, J = 15.5Hz, 1H), 8.13 (d, J =
6.61 Hz, 2H)
MS (ES-MS): 437.2 (M-1)
Example 5 :
Synthesis of 1-f2-methvloxv-4-chlorophenvn
•3-f3.5-dimethvi-4-carboxvdimethvlmethvloxyphenvnprop-2-en-1-one
The method enabled the preparation of said compound with an overall yield of
22%.
Synthesis of the chemical precursor:
1 -[2-methyloxy-4-chlorophenyl]
-3-[3,5-dimethyl-4-hydroxyphenyl]prop-2-en-1-one (Compound 13)
This compound was synthesized from 4-chloro-2-methoxyacetophenone and 3,5-
dimethyl-4-hydroxybenzaldehyde according to general method 1 described
hereinabove.
Purification was by silica gel chromatography (cyclohexane/ethyl acetate 85:15).
Yield : 72%
1H NMR DMSO 8 ppm : 2.21 (s, 6H), 3.90 (s, 3H), 7.12 (m, 1H), 7.23 (d, J =
15.5Hz, 1H), 7.29 (d, J = 1.80Hz, 1H), 7.38 (d, J = 15.5 Hz, 1H), 7.41 (s, 2H), 7.48
(d, J = 7.98Hz, 1H)
Synthesis of the tert-butvl ester
1 -[2-methyloxy-4-chlorophenyl]
-3-[3,5-dimethyl-4-tert-butyloxycarbonyldimethylmethyloxyphenyl]prop-2-en-1-one
(Compound 14)
This compound was synthesized from 1-[2-methyloxy-4-chlorophenyl]-3-[3,5-
dimethyl-4-hydroxydimethylmethyloxyphenyl]prop-2-en-1-one (Compound 13) and
tert-butyl bromoisobutyrate according to general method 2 described hereinabove.
Purification was by silica gel chromatography (cyclohexane/ethyl acetate 90:10).
Yield : 43%
Acid hydrolysis of the tert-butvl ester:
1 -[2-methyloxy-4-chlorophenyl]
-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-en-1-one (Compound
15)
This compound was synthesized from 1-[2-methoxy-4-chlorophenyl]-3-[3,5-
dimethyl-4-tert-butyloxycarbonyldimethylmethyloxyphenyl]prop-2-en-1-one
(Compound 14) according to general method 3 described hereinabove.
Purification was by silica gel chromatography (dichloromethane/methanol 98:2).
Yield : 70%
1H NMR DMSO 5 ppm : 1.38 (s, 6H), 2.19 (s, 6H), 3.89 (s, 3H), 7.12 (dd, J =
7.98, J = 1.71 Hz, 1H), 7.23 (d, J = 15.56HZ, 1H), 7.29 (d, J = 1.71 Hz, 1H), 7.38 (d,
J = 15.7 Hz, 1H), 7.41 (s, 2H), 7.48 (d, J = 7.98Hz, 1H)
MS(ES-MS):401.2(M-1)
Example 6 : Synthesis of 1-f4-bromophenvn-3-f3.5-dimethvl-4-
carboxvdimethvlmethvloxvphenvnprop-2-en-1-one
The method enabled the preparation of said compound with an overall yield of
21%.
Synthesis of the chemical precursor:
1-[4-bromophenyl]-3-[3,5-dimethyl-4-hydroxyphenyl]prop-2-en-1-one
(Compound 16)
This compound was synthesized from 4-bromoacetophenone and 3,5-dimethyl-4-
hydroxybenzaldehyde according to general method 1 described hereinabove.
Purification was by silica gel chromatography (cyclohexane/ethyl acetate 90:10).
Yield : 37%
1H NMR DMSO 8 ppm : 2.30 (s, 6H), 7.32 (s, 2H), 7.56-7.66 (m, 3H), 7.75 (d, J =
15.27HZ, 1H), 7.90 (d, J = 8.70Hz, 2H), 9.82 (s, 1H)
Synthesis of the tert-butvl ester:
1-[4-bromophenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1-one (Compound 17)
This compound was synthesized from 1-[4-bromophenyl]-3-[3,5-dimethyl-4-
hydroxyphenyl]prop-2-en-1-one (Compound 16) and tert-butyl bromoisobutyrate
according to general method 2 described hereinabove.
Purification was by silica gel chromatography (cyclohexane/ethyl acetate 90:10).
Yield : 75%
Acid hydrolysis of the tert-butvl ester:
1-[4-bromophenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-en-
1-one (Compound 18)
This compound was synthesized from 1-[4-bromophenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl]
prop-2-en-1 -one (Compound 17)
according to general method 3 described hereinabove.
Purification was by silica gel chromatography (dichloromethane/methanol 98:2).
Yield : 38 %
1H NMR DMSO 6 ppm : 1.39 (s, 6H), 2.22 (s, 6H), 7.58 (s, 2H), 7.65 (d, J =
15.39Hz, 1H), 7.84-7.77 (m, 3H), 8.09 (d, J = 8.19Hz, 2H), 13.01 (s, 1H)
MS(ES-MS):417.2(M-1)

WE CLAIM
1. Method of preparation of l,3-diphenylprop-2-en-l-one compounds substituted by a carboxyalkyloxy or carboxyalkylthio group of the following general formula:
(Formula Removed) in which
X1 represents a halogen or a -R1 group or a group corresponding to the
following formula : -G1-R1;
X2 represents a hydrogen atom or a thionitroso group or an alkyloxy group or an alkylcarbonyloxy group or an alkylthio group or an alkylcarbonylthio group;
X3 represents a -R3 group or a group corresponding to the following formula: G3-R3
X4 represents a halogen or a thionitroso group or a -R4 group or a group corresponding to the following formula: -G4-R4;
X5 represents a -R5 group or a group corresponding to the following formula : -G5-R5;
R1, R3, R4, R5, which are the same or different, represent a hydrogen atom or an alkyl group substituted or not by a carboxylic acid function;
G1, G3, G4, G5, which are the same or different, represent an oxygen or sulfur atom;
with one of the groups X1, X3, X4 or X5 corresponding to the formula -G-R, in which R is an alkyl group containing a carboxylic acid function wherein said method comprises the following steps :
(i) contacting a l,3-diphenylprop-2-en-l-one derivative substituted on one of the two phenyl groups by a hydroxyl or thiol group with a halogenated compound represented by general formula (II) :
(Formula Removed) in which Y represents a halogen atom, R is a C1-C24 alkyl chain and R' is a tert-
butyl group, chosen as acid-labile protective group of carboxylic acid;
(ii) acid hydrolysis of the ester obtained in step (i) with trifluoroacetic acid.
2. Method as claimed in claim 1, wherein the R group is a C1-C10 alkyl
chain, optionally substituted by one or more hydrocarbon groups, saturated,
linear or cyclic containing from 1 to 12 carbon atoms.
3. Method as claimed in any one of the previous claims, wherein step (i) is
carried out at a temperature comprised between 25 and 120°C and more
preferably between 80 and 120°C.
4. Method as claimed in any one of the previous claims, wherein step (i) is
carried out in the presence of a catalyst.
5. Method as claimed in any one of the previous claims, wherein step (i) is
carried out in the presence of cesium or potassium carbonate as catalyst.
6. Method as claimed in any one of the previous claims, wherein step (i) is
repeated by several additions of the halogenated compound represented by
general formula (II) and if necessary of the catalyst.
7. Method as claimed in any one of the previous claims, wherein the 1,3-
diphenylprop-2-en-l-one derivative substituted by a hydroxyl or thiol group,
which is used in step (i) is obtained by a Claisen-Schmidt reaction in acidic or
basic medium of a compound of the type acetophenone with a thio- or
hydroxybenzaldehyde derivative, or of a thio- or hydroxy-acetophenone
derivative with a compound of the benzaldehyde type.
8. Method as claimed in any one of the previous claims, wherein the
amount of trifluoroacetic acid which is used in step (ii) is from 1 to 20
equivalents, and preferably from 8 to 12 equivalents.
9. Method as claimed in any one of the previous claims, wherein step (ii) is
carried out at a temperature of 0 to 100°C and more preferably 18 to 25°C.